Neuroactive steroid concentrations are altered in various pathological conditions including ► depression, premenstrual ► dysphoric disorder, alcoholism and schizophrenia (Morrow 2007; Payne et al. 2008). However, the pathological significance of these alterations remains a matter of speculation. Because neuroactive steroids contribute to regulation of the HPA axis response to stress and are modulated by drugs that are used as medications for neuropsychiatric disease, neuroactive steroids may play a homeostatic role that both reflects and influences the allostatic state of the person and contributes to the wide range of symptomatology associated with all of these disease states.
Patients with major depression have elevated cortisol levels, hypersecretion of CRF and suppression of feedback mechanisms marked by blunted dexamethasone suppression of cortisol levels. Some neuroactive steroid concentrations are decreased in patients with major depression as well as in ► animal models of depression, and administration of antidepressant-specific serotonergic reuptake inhibitors increases these neuroactive steroids in patients and in rodent brain and plasma (see Rupprecht 2003, for review). This increase might be mediated by a direct effect of specific serotonergic reuptake inhibitors on the biosyn-thetic enzyme 3a-hydroxysteroid dehydrogenase that produces GABAergic neuroactive steroids or by increased serotonin neurotransmission that stimulates the release of CRF to activate the HPA axis. The acute anxiolytic and antidepressant-like effects of neuroactive steroids, demonstrated in rodent models, may be important for prevention and recovery from major depression. Hence, neuroactive steroids may contribute to the therapeutic efficacy of antidepressant medications by contributing to GABAergic inhibition, modulation of the HPA axis, as well as the unknown mechanisms that underlie their acute antidepressant-like activity.
Neuroactive steroid levels are also altered in premenstrual dysphoric disorder, although the literature is controversial with reports of increases, decreases, and no change in 3a,5a-THP plasma levels (see Girdler in Morrow 2007). Differences in analytical methods, diagnostic criteria or presence of other comorbid psychiatric disorders might account for these discrepancies. Premenstrual dysphoric disorder results in dysregulation of the HPA axis and sympathetic nervous system responses to stress. Furthermore, these patients have a blunted 3a,5a-THP response to stress. Women with a history of depression, regardless of premenstrual dysphoric disorder symptoms, also had a blunted 3a,5a-THP response to stress. All this experimental evidence emphasizes the important link between HPA axis function and neuroactive steroid levels in the maintenance of homeostasis and healthy brain function.
Like depression, alterations in HPA axis responsiveness are found in alcoholism during drinking and abstinence (see Morrow in Morrow 2007). ACTH and cortisol secretion increased during ethanol intoxication and acute alcohol withdrawal, but attenuated responsiveness of the HPA axis is found in both drinking and abstinent alcohol-dependent patients. Alcohol-dependent patients have low cortisol and 11-deoxycortisol basal levels, and have a reduced cortisol response to exogenous ACTH challenge. Moreover, they have attenuated ACTH and cortisol responses after pituitary stimulation by ovine or human CRF. Altered cortisol and ACTH responses to ovine CRF and naloxone have also been found in sons of alcoholics. The levels of the GABAergic neuroactive steroids have not been studied under these conditions, but are likely to be impacted since both human and animal studies show that neuroactive steroid responses to stress or HPA axis activation are blunted when ACTH or glucocorticoid responses are blunted. Basal levels of the GABAergic neuroactive steroid 3a,5a-THP are reduced during ethanol withdrawal in humans, when circulating cortisol levels are elevated. Furthermore, abstinent alcoholic patients show a blunted pregnenolone sulfate response to adrenal stimulation and a delayed deoxycorticosterone response to ovine CRF challenge, supporting the idea that blunting of the HPA axis also impacts the GABAergic neuroactive steroid responses to stress in alcoholics.
The levels of neuroactive steroid precursors pregnen-olone and DHEA as well as 3a,5a-THP have been studied in postmortem brain of patients with schizophrenia (see Payne et al. 2008, for review). Pregnenolone and 3a,5a-THP were present in human postmortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and DHEA levels were higher in both posterior cingulate and parietal cortex of subjects with schizophrenia versus control subjects. 3a,5a-THP levels tended to be decreased in parietal cortex in subjects with schizophrenia when compared with control subjects. Furthermore, pregnenolone, DHEA and 3a,5a-THP levels determined in human postmortem brain in these investigations are known to be physiologically relevant and therefore may have a functional impact on pathophysiology and not merely represent an epiphenomena. In addition, neuroactive steroid induction represents a potential mechanism contributing to the efficacy of clozapine and olanzapine, which in turn increase plasma pregnenolone and 3a,5a-THP levels in rodents. Clinical evidence suggests antipsychotic properties for neuroactive steroids. Progesterone administration ameliorates symptoms of postpartum psychosis in women. Furthermore, adjunct treatment with pregnenolone or 17p-estradiol improves schizophrenia symptomatology in both men and women. Most recently, two independent studies show that pregnenolone improves cognition and negative symptoms in patients with schizophrenia. These findings suggest that neuroactive steroids are candidate modulators of schizophrenia pathophysiology and/or therapeutics.
Progesterone and its GABAergic metabolites promote the viability of neurons in the brain and spinal cord. Neuroprotective effects have been documented in animal models of traumatic brain injury, experimentally induced ischemia, spinal cord lesions and Nieman-Pick type-C disease (see Schumacher et al. and Mellon in Morrow 2007). It is unknown if GABAergic neuroactive steroid levels are deficient or contribute to the etiology of these diseases, but their ability to promote recovery suggests a role in pathophysiology. Indeed, progesterone had remarkable efficacy in a clinical study of traumatic brain injury where it dramatically reduced mortality and increased recovery of function. This is a new area of avid investigation that will likely lead to a better understanding of the role of neuroactive steroids in health and disease.
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